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1.  Fracture Risk among Nursing Home Residents Initiating Antipsychotic Medications 
Objectives
to determine whether antipsychotic medication initiation is associated with subsequent fracture in nursing home residents, whether fracture rates differ between first-generation versus second-generation antipsychotic use, and whether fracture rates differ among users of haloperidol, risperidone, olanzapine, and quetiapine.
Design
time-to-event analyses were conducted in a retrospective cohort using linked Medicaid, Medicare, Minimum Data Set and Online Survey, Certification and Reporting data sets.
Setting and Participants
nursing home residents aged ≥ 65 years in CA, FL, MO, NJ and PA.
Measurements
fracture outcomes (any fracture; hip fracture) in first-versus second-generation antipsychotic users, and specifically among users of haloperidol, risperidone, olanzapine and quetiapine. Comparisons incorporated propensity scores that included patient-level variables (demographics, comorbidity, diagnoses, weight, fall history, concomitant medications, cognitive performance, physical function, aggressivebehavior) and facility-level variables (nursing home size, ownership factors, staffing levels).
Results
Among 8,262 subjects (within 4,131 pairs), 4.3% suffered any fracture during observation with 1% having a hip fracture during an average follow up period of 93 ± 71 days; range 1 to 293 days). Antipsychotic initiation was associated with any fracture (hazard ratio (HR) 1.39, p=0.004) and with hip fracture (HR 1.76, p=0.024). The highest risk was found for hip fracture when antipsychotic use was adjusted for dose(HR=2.96; p=0.008). However, no differences in time-to-fracture were found in first-versus second-generation agents or across competing individual drugs.
Conclusion
Antipsychotic initiation is associated with fracture in nursing home residents, but risk does not differ across commonly used antipsychotics.
doi:10.1111/jgs.12216
PMCID: PMC3656141  PMID: 23590366
fracture; antipsychotic; nursing home
2.  All-Cause Mortality Associated With Atypical and Conventional Antipsychotics Among Nursing Home Residents With Dementia: A Retrospective Cohort Study 
The Journal of clinical psychiatry  2009;70(10):1340-1347.
Objective
A recent meta-analysis has indicated that, in patients with dementia, the use of atypical antipsychotics is associated with an excess mortality. Later observational studies have suggested that conventional antipsychotics may pose an even greater risk of death. None of these studies could evaluate the risk associated with single antipsychotics nor could they provide any conclusive evidence concerning the risk among nursing home residents. We conducted a retrospective cohort study to compare the risk of death associated with atypical and conventional antipsychotics in a large population of nursing home residents with dementia.
Method
We identified 6,524 new users of atypical antipsychotics and 3,205 new users of conventional antipsychotics living in 1,581 Medicare- or Medicaid-certified nursing homes in 5 US states during the years 1998–2000. The outcome measure was all-cause mortality, which was determined during 6-months of follow-up.
Results
After adjusting for potential confounders relative to users of atypicals, the rate of death was increased for users of conventional antipsychotics (hazard ratio [HR], 1.26; 95% CI, 1.13–1.42). Relative to risperidone, a higher rate of death was documented for haloperidol (HR, 1.31; 95% CI, 1.13–1.53), phenothiazines (HR, 1.17; 95% CI, 1.00–1.38) and other conventional medications (HR, 1.32; 95% CI, 0.99–1.80). No atypical antipsychotic was associated with a differential risk relative to risperidone.
Conclusions
Conventional antipsychotics are associated with a higher risk of all-cause mortality than atypical agents. It seems advisable that they are not used in substitution for atypical antipsychotics among nursing home residents with dementia even when short-term therapy is being prescribed.
doi:10.4088/JCP.08m04597yel
PMCID: PMC3775351  PMID: 19906339
3.  Antipsychotics and the Risks of Sudden Cardiac Death and All-Cause Death: Cohort Studies in Medicaid and Dually-Eligible Medicaid-Medicare Beneficiaries of Five States 
Context
Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac risk, and torsade de pointes.
Objective
To examine the associations between antipsychotics and 1) outpatient-originated sudden cardiac death and ventricular arrhythmia (SD/VA) and 2) all-cause death.
Design
Two retrospective cohort studies
Setting
Medicaid programs of California, Florida, New York, Ohio and Pennsylvania.
Patients
Incident antipsychotic users aged 30–75 years.
Main Outcome Measures
1) Incident, first-listed emergency department or principal inpatient SD/VA diagnoses; and 2) death reported in the Social Security Administration Death Master File.
Results
Among 459,614 incident antipsychotic users, the incidences of SD/VA and death were 3.4 and 35.1 per 1,000 person-years, respectively. Compared to olanzapine as the referent, adjusted hazard ratios (HRs) for SD/VA were 2.06 (95% CI, 1.20–3.53) for chlorpromazine, 1.72 (1.28–2.31) for haloperidol, and 0.73 (0.57–0.93) for quetiapine. Adjusted HRs for perphenazine and risperidone were consistent with unity. In a subanalysis limited to first prescription exposures, HRs for chlorpromazine and haloperidol were further elevated (2.54 [1.07–5.99] and 2.68 [1.59–4.53], respectively), with the latter exhibiting a dose-response relationship. Results for death were similar.
Conclusions
Haloperidol and chlorpromazine had less favorable cardiac safety profiles than olanzapine. Among atypical agents, risperidone had a similar cardiac safety profile to olanzapine, whereas quetiapine was associated with 30% and 20% lower risks of SD/VA and death, respectively, compared to olanzapine. These measured risks do not correlate well with average QT prolongation, further supporting the notion that average QT prolongation may be a poor surrogate of antipsychotic arrhythmogenicity.
doi:10.4172/2155-9880.S10-006
PMCID: PMC3767168  PMID: 24027655
Antipsychotic agents; Cardiac arrhythmias; Cohort studies; Death; International classification of diseases; Medicaid; Pharmacoepidemiology; Proportional hazards models; Sudden death; Torsades de pointes
4.  Schizophrenia 
Clinical Evidence  2012;2012:1007.
Introduction
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (demotivation, self-neglect, and reduced emotion) have not been consistently improved by any treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for positive, negative, or cognitive symptoms of schizophrenia? What are the effects of drug treatments in people with schizophrenia who are resistant to standard antipsychotic drugs? What are the effects of interventions to improve adherence to antipsychotic medication in people with schizophrenia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 51 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amisulpride, chlorpromazine, clozapine, depot haloperidol decanoate, haloperidol, olanzapine, pimozide, quetiapine, risperidone, sulpiride, ziprasidone, zotepine, aripiprazole, sertindole, paliperidone, flupentixol, depot flupentixol decanoate, zuclopenthixol, depot zuclopenthixol decanoate, behavioural therapy, clozapine, compliance therapy, first-generation antipsychotic drugs in treatment-resistant people, multiple-session family interventions, psychoeducational interventions, and second-generation antipsychotic drugs in treatment-resistant people.
Key Points
The lifetime prevalence of schizophrenia is approximately 0.7% and incidence rates vary between 7.7 and 43.0 per 100,000; about 75% of people have relapses and continued disability, and one third fail to respond to standard treatment. Positive symptoms include auditory hallucinations, delusions, and thought disorder. Negative symptoms (anhedonia, asociality, flattening of affect, and demotivation) and cognitive dysfunction have not been consistently improved by any treatment.
Standard treatment of schizophrenia has been antipsychotic drugs, the first of which included chlorpromazine and haloperidol, but these so-called first-generation antipsychotics can all cause adverse effects such as extrapyramidal adverse effects, hyperprolactinaemia, and sedation. Attempts to address these adverse effects led to the development of second-generation antipsychotics.
The second-generation antipsychotics amisulpride, clozapine, olanzapine, and risperidone may be more effective at reducing positive symptoms compared with first-generation antipsychotic drugs, but may cause similar adverse effects, plus additional metabolic effects such as weight gain.
CAUTION: Clozapine has been associated with potentially fatal blood dyscrasias. Blood monitoring is essential, and it is recommended that its use be limited to people with treatment-resistant schizophrenia.
Pimozide, quetiapine, aripiprazole, sulpiride, ziprasidone, and zotepine seem to be as effective as standard antipsychotic drugs at improving positive symptoms. Again, these drugs cause similar adverse effects to first-generation antipsychotics and other second-generation antipsychotics.
CAUTION: Pimozide has been associated with sudden cardiac death at doses above 20 mg daily.
We found very little evidence regarding depot injections of haloperidol decanoate, flupentixol decanoate, or zuclopenthixol decanoate; thus, we don’t know if they are more effective than oral treatments at improving symptoms.
In people who are resistant to standard antipsychotic drugs, clozapine may improve symptoms compared with first-generation antipsychotic agents, but this benefit must be balanced against the likelihood of adverse effects. We found limited evidence on other individual first- or second-generation antipsychotic drugs other than clozapine in people with treatment-resistant schizophrenia.In people with treatment-resistant schizophrenia, we don't know how second-generation agents other than clozapine compare with each other or first-generation antipsychotic agents, or how clozapine compares with other second-generation antipsychotic agents, because of a lack of evidence.
We don't know whether behavioural interventions, compliance therapy, psychoeducational interventions, or family interventions improve adherence to antipsychotic medication compared with usual care because of a paucity of good-quality evidence.
It is clear that some included studies in this review have serious failings and that the evidence base for the efficacy of antipsychotic medication and other interventions is surprisingly weak. For example, although in many trials haloperidol has been used as the standard comparator, the clinical trial evidence for haloperidol is less impressive may be expected.
By their very nature, systematic reviews and RCTs provide average indices of probable efficacy in groups of selected individuals. Although some RCTs limit inclusion criteria to a single category of diagnosis, many studies include individuals with different diagnoses such as schizoaffective disorder. In all RCTs, even in those recruiting people with a single DSM or ICD-10 diagnosis, there is considerable clinical heterogeneity.
Genome-wide association studies of large samples with schizophrenia demonstrate that this clinical heterogeneity reflects, in turn, complex biological heterogeneity. For example, genome-wide association studies suggest that around 1000 genetic variants of low penetrance and other individually rare genetic variants of higher penetrance, along with epistasis and epigenetic mechanisms, are thought to be responsible, probably with the biological and psychological effects of environmental factors, for the resultant complex clinical phenotype. A more stratified approach to clinical trials would help to identify those subgroups that seem to be the best responders to a particular intervention.
To date, however, there is little to suggest that stratification on the basis of clinical characteristics successfully helps to predict which drugs work best for which people. There is a pressing need for the development of biomarkers with clinical utility for mental health problems. Such measures could help to stratify clinical populations or provide better markers of efficacy in clinical trials, and would complement the current use of clinical outcome scales. Clinicians are also well aware that many people treated with antipsychotic medication develop significant adverse effects such as extrapyramidal symptoms or weight gain. Again, our ability to identify which people will develop which adverse effects is poorly developed, and might be assisted by using biomarkers to stratify populations.
The results of this review tend to indicate that as far as antipsychotic medication goes, current drugs are of limited efficacy in some people, and that most drugs cause adverse effects in most people. Although this is a rather downbeat conclusion, it should not be too surprising, given clinical experience and our knowledge of the pharmacology of the available antipsychotic medication. All currently available antipsychotic medications have the same putative mechanism of action — namely, dopaminergic antagonism with varying degrees of antagonism at other receptor sites. More efficacious antipsychotic medication awaits a better understanding of the biological pathogenesis of these conditions so that rational treatments can be developed.
PMCID: PMC3385413  PMID: 23870705
5.  Comparative Safety of Antipsychotic Medications in Nursing Home Residents 
Background and Objectives
Nearly one-third of nursing home residents in the US receive antipsychotic medications, yet important questions remain concerning their safety. We sought to compare the risk of major medical events in residents newly initiated on conventional or atypical antipsychotics.
Design
Cohort study, using linked Medicaid, Medicare, Minimum Data Set and Online Survey Certification and Reporting data. Propensity score-adjusted proportional hazards models were used to compare risks for medical events at a class and individual drug level.
Setting
Nursing homes in 45 US states.
Participants
83,959 Medicaid eligible residents ≥65 who initiated antipsychotic treatment following nursing home admission in 2001-2005.
Interventions
Conventional and atypical antipsychotics.
Outcome measures
Hospitalization for myocardial infarction, cerebrovascular events, serious bacterial infections and hip fracture within 180 days of treatment initiation.
Results
Risks of bacterial infections (HR = 1.25, 95%CI 1.05-1.49) and possibly myocardial infarction (1.23, 95%CI 0.81-1.86) and hip fracture (1.29, 95%CI 0.95-1.76) were higher and risks of cerebrovascular events (0.82, 95%CI 0.65-1.02) were lower among patients initiating conventional compared to atypical agents. Little variation existed among individual atypical agents, except for a somewhat lower risk of cerebrovascular events with olanzapine (0.91, 95%CI 0.81-1.02) and quetiapine (0.89, 95%CI 0.79-1.02); a lower risk of bacterial infections (0.83, 95%CI 0.73-0.94) and possibly a higher risk of hip fracture (1.17, 95%CI 0.96-1.43) with quetiapine, all compared with risperidone. Dose-response relations were observed for all events (1.12, 95%CI 1.05-1.19 for high- vs low-dose for all events combined).
Conclusion
These associations underscore the importance of carefully selecting the specific antipsychotic agent and dose, and monitoring their safety, especially in nursing home residents who have an array of medical illnesses and receive complex medication regimens.
doi:10.1111/j.1532-5415.2011.03853.x
PMCID: PMC3302976  PMID: 22329464
Antipsychotics; nursing homes; safety; dementia
6.  Clozapine versus other atypical antipsychotics for schizophrenia 
Background
Clozapine is an atypical antipsychotic demonstrated to be superior in the treatment of refractory schizophrenia which causes fewer movement disorders. Clozapine, however, entails a significant risk of serious blood disorders such as agranulocytosis which could be potentially fatal. Currently there are a number of newer antipsychotics which have been developed with the purpose to find both a better tolerability profile and a superior effectiveness.
Objectives
To compare the clinical effects of clozapine with other atypical antipsychotics (such as amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) in the treatment of schizophrenia and schizophrenia-like psychoses.
Search methods
We searched the Cochrane Schizophrenia Groups Register (June 2007) and reference lists of all included randomised controlled trials. We also manually searched appropriate journals and conference proceedings relating to clozapine combination strategies and contacted relevant pharmaceutical companies.
Selection criteria
All relevant randomised, at least single-blind trials, comparing clozapine with other atypical antipsychotics, any dose and oral formulations, for people with schizophrenia or related disorders.
Data collection and analysis
We selected trials and extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD) again based on a random-effects model.
Main results
The review currently includes 27 blinded randomised controlled trials, which involved 3099 participants. Twelve randomised control trials compared clozapine with olanzapine, five with quetiapine, nine with risperidone, one with ziprasidone and two with zotepine. Attrition from these studies was high (overall 30.1%), leaving the interpretation of results problematic. Clozapine had a higher attrition rate due to adverse effects than olanzapine (9 RCTs, n=1674, RR 1.60 CI 1.07 to 2.40, NNT 25 CI 15 to 73) and risperidone (6 RCTs, n=627, RR 1.88 CI 1.11 to 3.21, NNT 16 CI 9 to 59). Fewer participants in the clozapine groups left the trials early due to inefficacy than risperidone (6 RCTs, n=627, RR 0.40 CI 0.23 to 0.70, NNT 11 CI 7 to 21), suggesting a certain higher efficacy of clozapine.
Clozapine was more efficacious than zotepine in improving the participants general mental state (BPRS total score: 1 RCT, n=59, MD −6.00 CI −9.83 to −2.17), but not consistently more than olanzapine, quetiapine, risperidone and ziprasidone. There was no significant difference between clozapine and olanzapine or risperidone in terms of positive or negative symptoms of schizophrenia. According to two studies from China quetiapine was more efficacious for negative symptoms than clozapine (2 RCTs, n=142, MD 2.23 CI 0.99 to 3.48).
Clozapine produced somewhat fewer extrapyramidal side-effects than risperidone (use of antiparkinson medication: 6 RCTs, n=304, RR 0.39 CI 0.22 to 0.68, NNT 7 CI 5 to 18) and zotepine (n=59, RR 0.05 CI 0.00 to 0.86, NNT 3 CI 2 to 5). More participants in the clozapine group showed decreased white blood cells than those taking olanzapine, more hypersalivation and sedation than those on olanzapine, risperidone and quetiapine and more seizures than people on olanzapine and risperidone. Also clozapine produced an important weight gain not seen with risperidone.
Other differences in adverse effects were less documented and should be replicated, for example, clozapine did not alter prolactin levels whereas olanzapine, risperidone and zotepine did; compared with quetiapine, clozapine produced a higher incidence of electrocardiogram (ECG) alterations; and compared with quetiapine and risperidone clozapine produced a higher increase of triglyceride levels. Other findings that should be replicated were: clozapine improved social functioning less than risperidone and fewer participants in the clozapine group had to be hospitalised to avoid suicide attempts compared to olanzapine.
Other important outcomes such as service use, cognitive functioning, satisfaction with care or quality of life were rarely reported.
Authors’ conclusions
Clozapine may be a little more efficacious than zotepine and risperidone but further trials are required to confirm this finding. Clozapine differs more clearly in adverse effects from other second generation antipsychotics and the side-effect profile could be key in the selection of treatment depending on the clinical situation and a patient’s preferences. Data on other important outcomes such as cognitive functioning, quality of life, death or service use are currently largely missing, making further large and well-designed trials necessary. It is also important to take into account that the large number of people leaving the studies early limits the validity and interpretation of our findings.
doi:10.1002/14651858.CD006633.pub2
PMCID: PMC4169186  PMID: 21069690
Antipsychotic Agents [* therapeutic use]; Benzodiazepines [therapeutic use]; Clozapine [* therapeutic use]; Dibenzothiazepines [therapeutic use]; Dibenzothiepins [therapeutic use]; Piperazines [therapeutic use]; Randomized Controlled Trials as Topic; Risperidone [therapeutic use]; Schizophrenia [* drug therapy]; Thiazoles [therapeutic use]; Humans
7.  Medical Care Costs and Hospitalization in Patients with Bipolar Disorder Treated with Atypical Antipsychotics 
American Health & Drug Benefits  2012;5(6):379-386.
Background
A large proportion of costs associated with the treatment of bipolar disorder are attributable to patient hospitalization.
Objective
To investigate medical care costs and hospitalization rates among patients with bipolar disorder who were managed with aripiprazole compared with olanzapine, quetiapine, risperidone, or ziprasidone.
Methods
This retrospective cohort study assessed patients who were aged 18 to 64 years, diagnosed with bipolar disorder, and who were receiving therapy with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone. This study was based on data from the PharMetrics claims database between January 1, 2003, and September 30, 2008. The study used a time-to-event framework. Cox proportional hazards models were used to assess the impact of each atypical antipsychotic on time to hospitalization, including all-cause and mental health–related reasons. Generalized linear models were used to compare costs per treated patient per month between the groups. Aripiprazole therapy was the reference group for all comparisons.
Results
Aripiprazole therapy showed a significantly lower hazard ratio (HR) for all-cause hospitalizations compared with olanzapine (HR, 1.4), quetiapine (HR, 1.4), risperidone (HR, 1.2), and ziprasidone (HR, 1.7); and for mental health–related hospitalizations compared with olanzapine, quetiapine, risperidone (HR, 1.3 each), and ziprasidone (HR, 1.7). Ziprasidone had higher unadjusted all-cause medical costs (US $1151 ± $2928) and unadjusted mental health–related costs (US $711 ± $2263) than the other antipsychotics that were included in this study, whereas aripiprazole had the lowest all-cause (US $804 ± $2523) and mental health–related costs (US $475 ± $2145) compared with the other antipsychotics. Quetiapine had the highest all-cause costs (US $1221; 95% confidence interval [CI], 1180–1263), and ziprasidone had the highest mental health–related costs (US $823; 95% CI, 754–898). Adjusted inpatient and emergency department all-cause costs were significantly lower for aripiprazole compared with all other atypical antipsychotics (P <.05), except olanzapine; however, the adjusted inpatient and emergency department mental health–related costs were significantly lower for aripiprazole only when compared with ziprasidone (P <.05).
Conclusions
The costs of medical care for patients with bipolar disorder differ based on the type of medication used, which can affect the rate of hospitalization. Treatment with aripiprazole was associated with fewer hospitalizations, longer time to hospitalization, and therefore the lowest all-cause and mental health–related medical costs compared with olanzapine, quetiapine, risperidone, or ziprasidone. Therefore, aripiprazole may offer an economic advantage over other atypical antipsychotics in patients with bipolar disorder.
PMCID: PMC4031693  PMID: 24991334
8.  Olanzapine versus other atypical antipsychotics for schizophrenia 
Background
In many countries of the industrialised world second generation (“atypical”) antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether, and if so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examined how the efficacy and tolerability of olanzapine differs from that of other second generation antipsychotics.
Objectives
To evaluate the effects of olanzapine compared to other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.
Search methods
1. Electronic searching
We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.
2. Reference searching
We inspected the reference of all identified studies for more trials.
3. Personal contact
We contacted the first author of each included study for missing information.
4. Drug companies
We contacted the manufacturers of all atypical antipsychotics included for additional data.
Selection criteria
We included all randomised trials that used at least single-blind (rater-blind) design, comparing oral olanzapine with oral forms of amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model.
Main results
The review currently includes 50 studies and 9476 participants which provided data for six comparisons (olanzapine compared to amisulpride, aripiprazole, clozapine, quetiapine, risperidone or ziprasidone). The overall attrition from the included studies was considerable (49.2%) leaving the interpretation of results problematic.
Olanzapine improved the general mental state (PANSS total score) more than aripiprazole (2 RCTs, n=794, WMD −4.96 CI −8.06 to −1.85), quetiapine (10 RCTs, n=1449, WMD −3.66 CI −5.39 to −1.93), risperidone (15 RCTs, n=2390, WMD −1.94 CI −3.31 to −0.58) and ziprasidone (4 RCTs, n=1291, WMD −8.32 CI −10.99 to −5.64), but not more than amisulpride or clozapine. This somewhat better efficacy was confirmed by fewer participants in the olanzapine groups leaving the studies early due to inefficacy of treatment compared to quetiapine (8 RCTs, n=1563, RR 0.56 CI 0.44 to 0.70, NNT 11 CI 6 to 50), risperidone (14 RCTs, n=2744, RR 0.78 CI 0.62 to 0.98, NNT 50 CI 17 to 100) and ziprasidone (5 RCTs, n=1937, RR 0.64 CI 0.51 to 0.79, NNT 17, CI 11 to 33).
Fewer participants in the olanzapine group than in the quetiapine (2 RCTs, n=876, RR 0.56 CI 0.41 to 0.77, NNT 11 CI 7 to 25) and ziprasidone (2 RCTs, n=766, RR 0.65 CI 0.45 to 0.93, NNT 17 CI 9 to 100) treatment groups, but not in the clozapine group (1 RCT, n=980, RR 1.28 CI 1.02 to 1.61, NNH not estimable), had to be re-hospitalised in the trials.
Except for clozapine, all comparators induced less weight gain than olanzapine (olanzapine compared to amisulpride: 3 RCTs, n=671, WMD 2.11kg CI 1.29kg to 2.94kg; aripiprazole: 1 RCT, n=90, WMD 5.60kg CI 2.15kg to 9.05kg; quetiapine: 7 RCTs, n=1173, WMD 2.68kg CI 1.10kg to 4.26kg; risperidone: 13 RCTs, n=2116, WMD 2.61kg CI 1.48kg to 3.74kg; ziprasidone: 5 RCTs, n=1659, WMD 3.82kg CI 2.96kg to 4.69kg). Associated problems such as glucose and cholesterol increase were usually also more frequent in the olanzapine group.
Other differences in adverse effects were less well documented. Nevertheless, olanzapine may be associated with slightly more extrapyramidal side effects than quetiapine (use of antiparkinson medication (6 RCTs, n=1090, RR 2.05 CI 1.26 to 3.32, NNH 25 CI 14 to 100), but less than risperidone (use of antiparkinson medication 13 RCTs, n=2599, RR 0.78 CI 0.65 to 0.95, NNH 17 CI 9 to 100) and ziprasidone (use of antiparkinson medication 4 RCTs, n=1732, RR 0.70 CI 0.50 to 0.97, NNH not estimable). It may also increase prolactin somewhat more than aripiprazole, clozapine and quetiapine, but clearly less so than risperidone (6 RCTs, n=1291, WMD −22.84 CI −27.98 to −17.69).
Authors’ conclusions
Olanzapine may be a somewhat more efficacious drug than some other second generation antipsychotic drugs. This small superiority in efficacy needs to be weighed against a larger weight gain and associated metabolic problems than most other second generation antipsychotic drugs, except clozapine. These conclusions are tentative due to the large number of people leaving the studies early which possibly limits the validity of the findings. Further large, well-designed trials are necessary to establish the relative effects of different second generation antipsychotic drugs.
doi:10.1002/14651858.CD006654.pub2
PMCID: PMC4169107  PMID: 20238348
Antipsychotic Agents [adverse effects; *therapeutic use]; Benzodiazepines [*therapeutic use]; Clozapine [therapeutic use]; Dibenzothiazepines [therapeutic use]; Piperazines [therapeutic use]; Quinolones [therapeutic use]; Risperidone [therapeutic use]; Schizophrenia [*drug therapy]; Sulpiride [analogs & derivatives; therapeutic use]; Thiazoles [therapeutic use]; Humans
9.  Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes 
PLoS Medicine  2013;10(3):e1001403.
In a systematic review and meta-analysis, Glen Spielmans and colleagues find that adjunctive atypical antipsychotic medications are associated with small-to-moderate improvements in depressive symptoms in patients with depression, but there is little evidence for improvement on measures of quality of life, and these medications are linked to adverse events such as weight gain.
Background
Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk–benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression.
Methods and Findings
We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48–2.73), OFC (OR, 1.42; 95% CI, 1.01–2.0), quetiapine (OR, 1.79; 95% CI, 1.33–2.42), and risperidone (OR, 2.37; 95% CI, 1.31–4.30).
The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58–2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87–1.93), quetiapine (OR, 1.53, 95% CI, 1.17–2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16–2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery–Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49).
Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events.
Conclusions
Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Everyone feels miserable occasionally. But for people who are clinically depressed, feelings of sadness and hopelessness and physical symptoms such as sleeping badly can last for months or years and can make them feel life is no longer worth living. Depression affects one in six people at some time during their life. Clinicians diagnose depression by asking their patients a series of questions about their feelings and symptoms. The answer to each question is given a score, and the total score from the questionnaire (“depression rating scale”) indicates the severity of depression. Treatment of depression often involves talking treatments (psychotherapy) such as cognitive behavioral therapy, which helps people change negative ways of thinking and behaving and antidepressant drugs, most commonly “selective serotonin reuptake inhibitors” such as fluoxetine and paroxetine.
Why Was This Study Done?
Atypical antipsychotic medications (for example, aripiprazole, olanzapine/fluoxetine combination [OFC], quetiapine, and risperidone) are also widely prescribed for the treatment of depression. These drugs, which were developed to treat mental illnesses that are characterized by a loss of contact with reality, are used as adjunctive therapy for depression. That is, they are used in addition to antidepressant drugs. Clinicians wrote nearly four million prescriptions for adjunctive treatment of depression with atypical antipsychotic medications in 2007–2008 in the US alone. However, it is not known whether the benefits of using these drugs to treat depression outweigh their side effects, which include weight gain, sedation, and akathisia (a feeling of inner restlessness resulting in an urge to move, which may or may not be accompanied by increased movement). Here, the researchers undertake a systematic review and meta-analysis of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 14 short-term randomized controlled trials (duration 4–12 weeks) that compared adjunctive antipsychotic medications (aripiprazole, OFC, quetiapine, or risperidone) to placebo (dummy drug) in the treatment of depression that had not responded to antidepressant medication alone. All four drugs had statistically significant effects (effects unlikely to have happened by chance) on remission, which was most commonly defined as a score of less than eight at the study end point on the Montgomery–Asberg Depression Rating Scale. The researchers calculated the number of patients that would have to be treated for one patient to achieve remission (number needed to treat, or NNT). For OFC, the NNT was 19; for all the other drugs it was nine. All the drugs except OFC also significantly improved response rates (defined as a 50% improvement in depression rating score). However, the medications provided little or no benefit in terms of functioning and quality of life, except for risperidone, which had a small-to-moderate effect on quality of life. Finally, treatment with atypical antipsychotic medications was linked to several adverse effects, including weight gain (all four drugs) and akathisia (aripiprazole).
What Do These Findings Mean?
These results suggest that atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms. However, clinicians should interpret this conclusion cautiously for several reasons. First, adjunctive treatment with atypical antipsychotics provided only small-to-moderate benefits. Moreover, shortcomings in study design and data reporting methods may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Second, this study provides little evidence that adjunctive treatment with atypical antipsychotics improves patients' quality of life or reduces their functional impairment. Finally, this study highlights abundant evidence of potential treatment-related harm. This evaluation of the safety and efficacy of adjunctive treatments for clinical depression provides critical insights that should help clinicians better understand the risk–benefit profiles of this approach to the treatment of major depressive disorder.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001403.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); it has a webpage on mental health medications that includes information about atypical antipsychotics
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from healthtalkonline.org
The UK charity Mind provides information on depression and on antipsychotic drugs; Mind also includes personal stories about depression on its website
MedlinePlus provides links to other resources about depression (in English and Spanish)
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
doi:10.1371/journal.pmed.1001403
PMCID: PMC3595214  PMID: 23554581
10.  Risk of Mortality Among Individual Antipsychotics in Patients with Dementia 
Objective
The use of antipsychotics to treat the behavioral symptoms of dementia is associated with increased mortality. However, there remains limited information regarding individual agents’ risks.
Method
This was a retrospective cohort study using national data from the US Department of Veterans Affairs (fiscal years 1999–2008) for patients ≥65 years old with dementia, beginning outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, and haloperidol) or valproic acid and its derivatives (as a non-antipsychotic comparison). The total sample included 33,604 patients. Individual drug groups were compared for 180-day mortality rates. Potential confounding was addressed using multivariate models and propensity adjustments.
Results
In covariate-adjusted intent to treat analyses, haloperidol users had the highest mortality rates (relative risk 1.54, 95% confidence interval 1.38–1.73) followed by risperidone (reference), olanzapine (RR 0.99, 95% CI 0.89–1.10), valproic acid and its derivatives (RR 0.91, 95% CI 0.78–1.06) and quetiapine (RR 0.73, 95% CI 0.67–0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage showed similar patterns. Haloperidol risk was highest in the first 30 days and then significantly and sharply decreased. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during 180-day follow-up.
Conclusions
There may be differences in mortality risks among individual antipsychotic agents. Further, the use of valproic acid and its derivatives as alternative agents to address the neuropsychiatric symptoms of dementia may carry associated risks as well.
doi:10.1176/appi.ajp.2011.11030347
PMCID: PMC4269551  PMID: 22193526
11.  Quetiapine versus other atypical antipsychotics for schizophrenia 
Background
In many countries of the industrialised world second generation (’atypical’) antipsychotic drugs have become the first line drug treatment for people with schizophrenia. It is not clear how the effects of the various second generation antipsychotic drugs differ.
Objectives
To evaluate the effects of quetiapine compared with other second generation antipsychotic drugs for people with schizophrenia and schizophrenia-like psychosis.
Search methods
We searched the Cochrane Schizophrenia Group Trials Register (April 2007), inspected references of all identified studies, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information.
Selection criteria
We included all randomised control trials comparing oral quetiapine with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random-effects model.
Main results
The review currently includes 21 randomised control trials (RCTs) with 4101 participants. These trials provided data on four comparisons - quetiapine versus clozapine, olanzapine, risperidone or ziprasidone.
A major limitation to all findings is the high number of participants leaving studies prematurely (57.6%) and the substantial risk of biases in studies. Efficacy data favoured olanzapine and risperidone compared with quetiapine (PANSS total score versus olanzapine:10 RCTs, n=1449, WMD 3.66 CI 1.93 to 5.39; versus risperidone: 9 RCTs, n=1953, WMD 3.09 CI 1.01 to 5.16), but clinical meaning is unclear. There were no clear mental state differences when quetiapine was compared with clozapine or ziprasidone.
Compared with olanzapine, quetiapine produced slightly fewer movement disorders (6 RCTs, n=1090, RR use of antiparkinson medication 0.49 CI 0.3 to 0.79, NNH 25 CI 14 to 100) and less weight gain (7 RCTs, n=1173, WMD −2.81 CI −4.38 to −1.24) and glucose elevation, but more QTc prolongation (3 RCTs, n=643, WMD 4.81 CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (6 RCTs, n=1715, RR use of antiparkinson medication 0.5 CI 0.3 to 0.86, NNH 20 CI 10 to 100), less prolactin increase (6 RCTs, n=1731, WMD −35.28 CI −44.36 to −26.19) and some related adverse effects, but more cholesterol increase (5 RCTs, n=1433, WMD 8.61 CI 4.66 to 12.56). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n=522, RR use of antiparkinson medication 0.43 CI 0.2 to 0.93, NNH not estimable) and prolactin increase. On the other hand quetiapine was more sedating and led to more weight gain (2 RCTs, n=754, RR 2.22 CI 1.35 to 3.63, NNH 13 CI 8 to 33) and cholesterol increase than ziprasidone.
Authors’ conclusions
Best available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks. Comparisons with amisulpride, aripiprazole, sertindole and zotepine do not exist. Most data that has been reported within existing comparisons are of very limited value because of assumptions and biases within them. There is much scope for further research into the effects of this widely used drug.
doi:10.1002/14651858.CD006625.pub2
PMCID: PMC4167871  PMID: 20091600
Antipsychotic Agents [adverse effects; * therapeutic use]; Benzodiazepines [adverse effects; therapeutic use]; Clozapine [adverse effects; therapeutic use]; Dibenzothiazepines [adverse effects; * therapeutic use]; Medication Adherence [statistics & numerical data]; Piperazines [adverse effects; therapeutic use]; Randomized Controlled Trials as Topic; Risperidone [adverse effects; therapeutic use]; Schizophrenia [* drug therapy]; Thiazoles [adverse effects; therapeutic use]; Humans
12.  Risperidone versus other atypical antipsychotics for schizophrenia 
Background
In many countries of the industrialised world second-generation (“atypical”) antipsychotics (SGAs) have become the first line drug treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs.
Objectives
To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.
Search methods
1. Electronic searching
We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.
2. Reference searching
We inspected the references of all identified studies for more trials.
3. Personal contact
We contacted the first author of each included study for missing information.
4. Drug companies
We contacted the manufacturers of all atypical antipsychotics included for additional data.
Selection criteria
We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD), again based on a random-effects model.
Main results
The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with quetiapine, two with sertindole, three with ziprasidone and none with zotepine. Attrition from these studies was high (46.9%), leaving the interpretation of results problematic. Furthermore, 60% were industry sponsored, which can be a source of bias.
There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard.
Risperidone improved the general mental state (PANSS total score) slightly less than olanzapine (15 RCTs, n = 2390, MD 1.94 CI 0.58 to 3.31), but slightly more than quetiapine (9 RCTs, n = 1953, MD −3.09 CI −5.16 to −1.01) and ziprasidone (3 RCTs, n = 1016, MD −3.91 CI −7.55 to −0.27). The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same outcome.
Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs (use of antiparkinson medication versus clozapine 6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48, NNH 6 CI 33 to 3; versus olanzapine 13 RCTs, n = 2599, RR 1.28 CI 1.06 to 1.55, NNH 17 CI 9 to 100; versus quetiapine 6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 100; versus ziprasidone 2 RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable; parkinsonism versus sertindole 1 RCT, n = 321, RR 4.11 CI 1.44 to 11.73, NNH 14 CI 100 to 8). Risperidone also increased prolactin levels clearly more than all comparators, except for amisulpride and sertindole for which no data were available.
Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic problems than amisulpride (weight gain: 3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61), aripiprazole (cholesterol increase: 1 RCT, n = 83, MD 22.30 CI 4.91 to 39.69) and ziprasidone (cholesterol increase 2 RCTs, n = 767, MD 8.58 CI 1.11 to 16.04) but less than clozapine (weight gain 3 RCTs n = 373, MD −3.30 CI −5.65 to −0.95), olanzapine (weight gain 13 RCTs, n = 2116, MD −2.61 CI −3.74 to −1.48), quetiapine (cholesterol increase: 5 RCTs, n = 1433, MD −8.49 CI −12. 23 to −4.75) and sertindole (weight gain: 2 RCTs, n = 328, MD −0.99 CI −1.86 to −0.12). It may be less sedating than clozapine and quetiapine, lengthen the QTc interval less than sertindole (QTc change: 2 RCTs, n = 495, MD −18.60 CI −22.37 to 14.83), produce fewer seizures than clozapine (2 RCTs, n = 354, RR 0.22 CI 0.07 to 0.70, NNT 14 CI 8 to 33) and less sexual dysfunction in men than sertindole (2 RCTs, n = 437, RR 0.34 CI 0.16 to 0.76, NNT 13 CI 8 to 33).
Authors’ conclusions
Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other SGAs. It may also differ from other compounds in efficacy and in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions. Further large trials, especially comparing risperidone with those other new drugs for which only a few RCTs are available, are needed.
doi:10.1002/14651858.CD006626.pub2
PMCID: PMC4167865  PMID: 21249678
Antipsychotic Agents [adverse effects; * therapeutic use]; Benzodiazepines [therapeutic use]; Clozapine [therapeutic use]; Dibenzothiazepines [therapeutic use]; Imidazoles [therapeutic use]; Indoles [therapeutic use]; Piperazines [therapeutic use]; Quinolones [therapeutic use]; Randomized Controlled Trials as Topic; Risperidone [adverse effects; * therapeutic use]; Schizophrenia [* drug therapy]; Sulpiride [analogs & derivatives; therapeutic use]; Thiazoles [therapeutic use]; Humans
13.  Movement Disorders in Elderly Users of Risperidone and First Generation Antipsychotic Agents: A Canadian Population-Based Study 
PLoS ONE  2013;8(5):e64217.
Background
Despite concerns over the potential for severe adverse events, antipsychotic medications remain the mainstay of treatment of behaviour disorders and psychosis in elderly patients. Second-generation antipsychotic agents (SGAs; e.g., risperidone, olanzapine, quetiapine) have generally shown a better safety profile compared to the first-generation agents (FGAs; e.g., haloperidol and phenothiazines), particularly in terms of a lower potential for involuntary movement disorders. Risperidone, the only SGA with an official indication for the management of inappropriate behaviour in dementia, has emerged as the antipsychotic most commonly prescribed to older patients. Most clinical trials evaluating the risk of movement disorders in elderly patients receiving antipsychotic therapy have been of limited sample size and/or of relatively short duration. A few observational studies have produced inconsistent results.
Methods
A population-based retrospective cohort study of all residents of the Canadian province of Manitoba aged 65 and over, who were dispensed antipsychotic medications for the first time during the time period from April 1, 2000 to March 31, 2007, was conducted using Manitoba's Department of Health's administrative databases. Cox proportional hazards models were used to determine the risk of extrapyramidal symptoms (EPS) in new users of risperidone compared to new users of FGAs.
Results
After controlling for potential confounders (demographics, comorbidity and medication use), risperidone use was associated with a lower risk of EPS compared to FGAs at 30, 60, 90 and 180 days (adjusted hazard ratios [HR] 0.38, 95% CI: 0.22–0.67; 0.45, 95% CI: 0.28–0.73; 0.50, 95% CI: 0.33–0.77; 0.65, 95% CI: 0.45–0.94, respectively). At 360 days, the strength of the association weakened with an adjusted HR of 0.75, 95% CI: 0.54–1.05.
Conclusions
In a large population of elderly patients the use of risperidone was associated with a lower risk of EPS compared to FGAs.
doi:10.1371/journal.pone.0064217
PMCID: PMC3656145  PMID: 23696870
14.  Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients 
Background
Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients. We assessed the short-term mortality in a population-based cohort of elderly people in British Columbia who were prescribed conventional and atypical antipsychotic medications.
Methods
We used linked health care utilization data of all BC residents to identify a cohort of people aged 65 years and older who began taking antipsychotic medications between January 1996 and December 2004 and were free of cancer. We compared the 180-day all-cause mortality between residents taking conventional antipsychotic medications and those taking atypical antipsychotic medications.
Results
Of 37 241 elderly people in the study cohort, 12 882 were prescribed a conventional antipsychotic medication and 24 359 an atypical formulation. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% confidence interval [CI] 1.39–1.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.23–1.42). In comparison with risperidone, haloperidol was associated with the greatest increase in mortality (mortality ratio 2.14, 95% CI 1.86–2.45) and loxapine the lowest (mortality ratio 1.29, 95% CI 1.19–1.40). The greatest increase in mortality occurred among people taking higher (above median) doses of conventional antipsychotic medications (mortality ratio 1.67, 95% CI 1.50–1.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95% CI 1.42–1.80). Results were confirmed in propensity score analyses and instrumental variable estimation, minimizing residual confounding.
Interpretation
Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the risk of death associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients.
doi:10.1503/cmaj.061250
PMCID: PMC1800321  PMID: 17325327
15.  Ziprasidone versus other atypical antipsychotics for schizophrenia 
Background
In many countries of the industrialised world second generation (‘atypical’) antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether, and if so how much, the effects of the various new generation antipsychotics differ is a matter of debate. In this review we examined how the efficacy and tolerability of ziprasidone differs from that of other second generation antipsychotics.
Objectives
To evaluate the effects of ziprasidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses.
Search methods
We searched the Cochrane Schizophrenia Group Specialised Register (April 2007) and references of all identified studies for further trial citations. We contacted pharmaceutical companies and authors of trials for additional information.
This search was updated July 2012, 254 citations added to awaiting classification section.
Selection criteria
We included all randomised, at least single-blind, controlled trials comparing oral ziprasidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone or zotepine in people with schizophrenia or schizophrenia-like psychoses.
Data collection and analysis
We extracted data independently. For continuous data, we calculated weighted mean differences (MD) for dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate.
Main results
The review currently includes nine randomised controlled trials (RCTs) with 3361 participants. The overall rate of premature study discontinuation was very high (59.1%). Data for the comparisons of ziprasidone with amisulpride, clozapine, olanzapine, quetiapine and risperidone were available. Ziprasidone was a less acceptable treatment than olanzapine (leaving the studies early for any reason: 5 RCTs, n=1937, RR 1.26 CI 1.18 to 1.35, NNH 7 CI 5 to 10) and risperidone (3 RCTs, n=1029, RR 1.11 CI 1.02 to 1.20, NNH 14 CI 8 to 50), but not than the other second generation antipsychotic drugs. Ziprasidone was less efficacious than amisulpride (leaving the study early due to inefficacy: 1 RCT, n=123, RR 4.72 CI 1.06 to 20.98, NNH 8 CI 5 to 50) olanzapine (PANSS total score: 4 RCTs, n=1291, MD 8.32 CI 5.64 to 10.99) and risperidone (PANSS total score: 3 RCTs, n=1016, MD 3.91 CI 0.27 to 7.55). Based on limited data there were no significant differences in tolerability between ziprasidone and amisulpride or clozapine. Ziprasidone produced less weight gain than olanzapine (5 RCTs, n=1659, MD −3.82 CI −4.69 to −2.96), quetiapine (2 RCTs, n=754, RR 0.45 CI 0.28 to 0.74) or risperidone (3 RCTs, n=1063, RR 0.49 CI 0.33 to 0.74). It was associated with less cholesterol increase than olanzapine, quetiapine and risperidone. Conversely ziprasidone produced slightly more extrapyramidal side-effects than olanzapine (4 RCTs, n=1732, RR 1.43 CI 1.03 to 1.99, NNH not estimable) and more prolactin increase than quetiapine (2 RCTs, n=754, MD 4.77 CI 1.37 to 8.16), but less movement disorders (2 RCTs, n=822, RR 0.70 CI 0.51 to 0.97, NNT not estimable) and less prolactin increase (2 RCTs, n=767, MD −21.97 CI −27.34 to −16.60) than risperidone.
Note: the 254 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.
Authors’ conclusions
Ziprasidone may be a slightly less efficacious antipsychotic drug than amisulpride, olanzapine and risperidone. Its main advantage is the low propensity to induce weight gain and associated adverse effects. However, the high overall rate of participants leaving the studies early limits the validity of any findings.
doi:10.1002/14651858.CD006627.pub2
PMCID: PMC4164848  PMID: 19821380
Antipsychotic Agents [adverse effects; *therapeutic use]; Benzodiazepines [therapeutic use]; Clozapine [therapeutic use]; Dibenzothiazepines [therapeutic use]; Piperazines [adverse effects; *therapeutic use]; Randomized Controlled Trials as Topic; Risperidone [therapeutic use]; Schizophrenia [*drug therapy]; Sulpiride [analogs & derivatives; therapeutic use]; Thiazoles [adverse effects; *therapeutic use]; Humans
16.  One-year risk of psychiatric hospitalization and associated treatment costs in bipolar disorder treated with atypical antipsychotics: a retrospective claims database analysis 
BMC Psychiatry  2011;11:6.
Background
This study compared 1-year risk of psychiatric hospitalization and treatment costs in commercially insured patients with bipolar disorder, treated with aripiprazole, ziprasidone, olanzapine, quetiapine or risperidone.
Methods
This was a retrospective propensity score-matched cohort study using the Ingenix Lab/Rx integrated insurance claims dataset. Patients with bipolar disorder and 180 days of pre-index enrollment without antipsychotic exposure who received atypical antipsychotic agents were followed for up to 12 months following the initial antipsychotic prescription. The primary analysis used Cox proportional hazards regression to evaluate time-dependent risk of hospitalization, adjusting for age, sex and pre-index hospitalization. Generalized gamma regression compared post-index costs between treatment groups.
Results
Compared to aripiprazole, ziprasidone, olanzapine and quetiapine had higher risks for hospitalization (hazard ratio 1.96, 1.55 and 1.56, respectively; p < 0.05); risperidone had a numerically higher but not statistically different risk (hazard ratio 1.37; p = 0.10). Mental health treatment costs were significantly lower for aripiprazole compared with ziprasidone (p = 0.004) and quetiapine (p = 0.007), but not compared to olanzapine (p = 0.29) or risperidone (p = 0.80). Total healthcare costs were significantly lower for aripiprazole compared to quetiapine (p = 0.040) but not other comparators.
Conclusions
In commercially insured adults with bipolar disorder followed for 1 year after initiation of atypical antipsychotics, treatment with aripiprazole was associated with a lower risk of psychiatric hospitalization than ziprasidone, quetiapine, olanzapine and risperidone, although this did not reach significance with the latter. Aripiprazole was also associated with significantly lower total healthcare costs than quetiapine, but not the other comparators.
doi:10.1186/1471-244X-11-6
PMCID: PMC3036592  PMID: 21214937
17.  Comparative Effectiveness of Second-Generation Antipsychotic Medications in Early-Onset Schizophrenia 
Schizophrenia Bulletin  2011;38(4):845-853.
Scant information exists to guide pharmacological treatment of early-onset schizophrenia. We examine variation across commonly prescribed second-generation antipsychotic medications in medication discontinuation and psychiatric hospital admission among children and adolescents clinically diagnosed with schizophrenia. A 45-state Medicaid claims file (2001–2005) was analyzed focusing on outpatients, aged 6–17 years, diagnosed with schizophrenia or a related disorder prior to starting a new episode of antipsychotic monotherapy with risperidone (n = 805), olanzapine (n = 382), quetiapine (n = 260), aripiprazole (n = 173), or ziprasidone (n = 125). Cox proportional hazard regressions estimated adjusted hazard ratios of 180-day antipsychotic medication discontinuation and 180-day psychiatric hospitalization for patients treated with each medication. During the first 180 days following antipsychotic initiation, most youth treated with quetiapine (70.7%), ziprasidone (73.3%), olanzapine (73.7%), risperidone (74.7%), and aripirazole (76.5%) discontinued their medication (χ2 = 1.69, df = 4, P = .79). Compared with risperidone, the adjusted hazards of antipsychotic discontinuation did not significantly differ for any of the 4-comparator medications. The percentages of youth receiving inpatient psychiatric treatment while receiving their initial antipsychotic medication ranged from 7.19% (aripiprazole) to 9.89% (quetiapine) (χ2 = 0.79, df = 4, P = .94). As compared with risperidone, the adjusted hazard ratio of psychiatric hospital admission was 0.96 (95% CI: 0.57–1.61) for olanzapine, 1.03 (95% CI: 0.59–1.81) for quetiapine, 0.85 (95% CI: 0.43–1.70) for aripiprazole, and 1.22 (95% CI: 0.60–2.51) for ziprasidone. The results suggest that rapid antipsychotic medication discontinuation and psychiatric hospital admission are common in the community treatment of early-onset schizophrenia. No significant differences were detected in risk of either adverse outcome across 5 commonly prescribed second-generation antipsychotic medications.
doi:10.1093/schbul/sbq172
PMCID: PMC3406514  PMID: 21307041
schizophrenia; child psychiatry; antipsychotics; comparative effectiveness
18.  Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose? 
BMC Psychiatry  2011;11:197.
Background
The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose.
Methods
Patients were ≥18 years of age from three US healthcare systems and exposed to an SGA for ≥45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.
49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference.
Results
Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile.
Conclusions
In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers.
doi:10.1186/1471-244X-11-197
PMCID: PMC3264670  PMID: 22171594
19.  Long-term cost-effectiveness of atypical antipsychotics in the treatment of adults with schizophrenia in the US 
Background
The purpose of this study was to evaluate the long-term cost-effectiveness (including hospitalizations and cardiometabolic consequences) of atypical antipsychotics among adults with schizophrenia.
Methods
A 5-year Markov cohort cost-effectiveness model, from a US payer perspective, was developed to compare lurasidone, generic risperidone, generic olanzapine, generic ziprasidone, aripiprazole, and quetiapine extended-release. Health states included in the model were patients: on an initial atypical antipsychotic; switched to a second atypical antipsychotic; and on clozapine after failing a second atypical antipsychotic. Incremental cost-effectiveness ratios (ICERs) assessed incremental cost/hospitalization avoided. Effectiveness inputs included discontinuations, hospitalizations, weight change, and cholesterol change from comparative clinical trials for lurasidone and for aripiprazole, and the Clinical Antipsychotic Trials of Intervention Effectiveness for other comparators. Atypical antipsychotic-specific relative risk of diabetes obtained from a retrospective analysis was used to predict cardiometabolic events per Framingham body mass index risk equation. Mental health costs (relapsing versus nonrelapsing patients) and medical costs associated with cardiometabolic consequences (cardiovascular events and diabetes management) were obtained from published sources. Atypical antipsychotic costs were estimated from Red Book® prices at dose(s) reported in clinical data sources used in the model (weighted average dose of lurasidone and average dose for all other comparators). Costs and outcomes were discounted at 3%, and model robustness was tested using one-way and probabilistic sensitivity analyses.
Results
Ziprasidone, olanzapine, quetiapine extended-release, and aripiprazole were dominated by other comparators and removed from the comparative analysis. ICER for lurasidone versus risperidone was $25,884/relapse-related hospitalization avoided. At a $50,000 willingness-to-pay threshold, lurasidone has an 86.5% probability of being cost-effective, followed by a 7.2% probability for olanzapine, and 6.3% for risperidone. One-way sensitivity analysis showed the model is sensitive to lurasidone and generic risperidone hospitalization rates.
Conclusion
Generic risperidone is the least costly atypical antipsychotic. Lurasidone is more costly and more effective than risperidone and is cost-effective at willingness-to-pay thresholds of greater than $25,844 per hospitalization avoided. The favorable cost-effectiveness of lurasidone is driven by its clinical benefits (eg, efficacy in preventing hospitalizations in patients with schizophrenia) and its minimal cardiometabolic adverse effect profile.
doi:10.2147/CEOR.S47990
PMCID: PMC3775636  PMID: 24049452
cost-effectiveness; economic; model; schizophrenia; atypical antipsychotic
20.  Potential bias in testing for hyperprolactinemia and pituitary tumors in risperidone-treated patients: a claims-based study 
Background
A reporting association of risperidone with pituitary tumors has been observed. Because such tumors are highly prevalent, there may be other reasons why they were revealed in association with risperidone treatment. We assessed two potential explanations: disproportionately more prolactin assessment and head/brain imaging in risperidone-treated patients vs patients treated with other antipsychotics.
Methods
Treatment episodes with risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole, haloperidol, perphenazine and 'other typical' antipsychotics were identified in two databases (large commercial, Medicaid). Comparisons used proportional hazards regression to determine whether prolactin testing was disproportionate with risperidone, regardless of prior potentially prolactin-related adverse events (PPAEs). Logistic regression determined whether magnetic resonance imaging (MRI)/computed tomography (CT) were disproportionate in risperidone-treated patients vs other patients, regardless of hyperprolactinemia or PPAEs. In each regression, the 'other typical' antipsychotic category served as the comparator. Regression models controlled for age, gender, and other factors.
Results
Altogether, 197,926 treatment episodes were analyzed (63,878 risperidone). Among patients with or without preceding PPAEs, risperidone treatment was associated with a significantly greater likelihood of prolactin assessment (hazard ratio (HR) 1.34, 95% confidence interval (CI) = 1.09 to 1.66, p = 0.007). Among patients with hyperprolactinemia or PPAEs, those treated with risperidone (odds ratio (OR) 1.66, 95% CI 1.23 to 2.23, p = 0.001) or ziprasidone (OR 1.66, 95% CI 1.06 to 2.62, p = 0.028) had a higher likelihood of MRI/CT.
Conclusion
Risperidone-treated patients are more likely to undergo prolactin assessment regardless of prior PPAEs, and more likely to undergo MRI/CT in association with hyperprolactinemia or PPAEs. Thus, a predisposition for more evaluations in risperidone-treated patients may contribute to disproportionate identification and reporting of prevalent pituitary adenoma.
doi:10.1186/1744-859X-8-5
PMCID: PMC2649125  PMID: 19210771
21.  Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database 
PLoS Medicine  2012;9(3):e1001189.
A comparison of data held by the U.S. Food and Drug Administration (FDA) against data from journal reports of clinical trials enables estimation of the extent of publication bias for antipsychotics.
Background
Publication bias compromises the validity of evidence-based medicine, yet a growing body of research shows that this problem is widespread. Efficacy data from drug regulatory agencies, e.g., the US Food and Drug Administration (FDA), can serve as a benchmark or control against which data in journal articles can be checked. Thus one may determine whether publication bias is present and quantify the extent to which it inflates apparent drug efficacy.
Methods and Findings
FDA Drug Approval Packages for eight second-generation antipsychotics—aripiprazole, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, risperidone long-acting injection (risperidone LAI), and ziprasidone—were used to identify a cohort of 24 FDA-registered premarketing trials. The results of these trials according to the FDA were compared with the results conveyed in corresponding journal articles. The relationship between study outcome and publication status was examined, and effect sizes derived from the two data sources were compared. Among the 24 FDA-registered trials, four (17%) were unpublished. Of these, three failed to show that the study drug had a statistical advantage over placebo, and one showed the study drug was statistically inferior to the active comparator. Among the 20 published trials, the five that were not positive, according to the FDA, showed some evidence of outcome reporting bias. However, the association between trial outcome and publication status did not reach statistical significance. Further, the apparent increase in the effect size point estimate due to publication bias was modest (8%) and not statistically significant. On the other hand, the effect size for unpublished trials (0.23, 95% confidence interval 0.07 to 0.39) was less than half that for the published trials (0.47, 95% confidence interval 0.40 to 0.54), a difference that was significant.
Conclusions
The magnitude of publication bias found for antipsychotics was less than that found previously for antidepressants, possibly because antipsychotics demonstrate superiority to placebo more consistently. Without increased access to regulatory agency data, publication bias will continue to blur distinctions between effective and ineffective drugs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
People assume that, when they are ill, health-care professionals will ensure that they get the best available treatment. But how do clinicians know which treatment is likely to be most effective? In the past, clinicians used their own experience to make such decisions. Nowadays, they rely on evidence-based medicine—the systematic review and appraisal of trials, studies that investigate the efficacy and safety of medical interventions in patients. Evidence-based medicine can guide clinicians, however, only if all the results from clinical trials are published in an unbiased manner. Unfortunately, “publication bias” is common. For example, the results of trials in which a new drug did not perform better than existing drugs or in which it had unwanted side effects often remain unpublished. Moreover, published trials can be subject to outcome reporting bias—the publication may only include those trial outcomes that support the use of the new treatment rather than presenting all the available data.
Why Was This Study Done?
If only strongly positive results are published and negative results and side-effects remain unpublished, a drug will seem safer and more effective than it is in reality, which could affect clinical decision-making and patient outcomes. But how big a problem is publication bias? Here, researchers use US Food and Drug Administration (FDA) reviews as a benchmark to quantify the extent to which publication bias may be altering the apparent efficacy of second-generation antipsychotics (drugs used to treat schizophrenia and other mental illnesses that are characterized by a loss of contact with reality). In the US, all new drugs have to be approved by the FDA before they can be marketed. During this approval process, the FDA collects and keeps complete information about premarketing trials, including descriptions of their design and prespecified outcome measures and all the data collected during the trials. Thus, a comparison of the results included in the FDA reviews for a group of trials and the results that appear in the literature for the same trials can provide direct evidence about publication bias.
What Did the Researchers Do and Find?
The researchers identified 24 FDA-registered premarketing trials that investigated the use of eight second-generation antipsychotics for the treatment of schizophrenia or schizoaffective disorder. They searched the published literature for reports of these trials, and, by comparing the results of these trials according to the FDA with the results in the published articles, they examined the relationship between the study outcome (did the FDA consider it positive or negative?) and publication and looked for outcome reporting bias. Four of the 24 FDA-registered trials were unpublished. Three of these unpublished trials failed to show that the study drug was more effective than a placebo (a “dummy” pill); the fourth showed that the study drug was inferior to another drug already in use in the US. Among the 20 published trials, the five that the FDA judged not positive showed some evidence of publication bias. However, the association between trial outcome and publication status did not reach statistical significance (it might have happened by chance), and the mean effect size (a measure of drug effectiveness) derived from the published literature was only slightly higher than that derived from the FDA records. By contrast, within the FDA dataset, the mean effect size of the published trials was approximately double that of the unpublished trials.
What Do These Findings Mean?
The accuracy of these findings is limited by the small number of trials analyzed. Moreover, this study considers only the efficacy and not the safety of these drugs, it assumes that the FDA database is complete and unbiased, and its findings are not generalizable to other conditions that antipsychotics are used to treat. Nevertheless, these findings show that publication bias in the reporting of trials of second-generation antipsychotic drugs enhances the apparent efficacy of these drugs. Although the magnitude of the publication bias seen here is less than that seen in a similar study of antidepressant drugs, these findings show how selective reporting of clinical trial data undermines the integrity of the evidence base and can deprive clinicians of accurate data on which to base their prescribing decisions. Increased access to FDA reviews, suggest the researchers, is therefore essential to prevent publication bias continuing to blur distinctions between effective and ineffective drugs.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001189.
The US Food and Drug Administration provides information about drug approval in the US for consumers and health-care professionals
Detailed information about the process by which drugs are approved is on the web site of the FDA Center for Drug Evaluation and Research; also, FDA Drug Approval Packages are available for many drugs; the FDA Transparency Initiative, which was launched in June 2009, is an agency-wide effort to improve the transparency of the FDA
FDA-approved product labeling on drugs marketed in the US can be found at the US National Library of Medicine's DailyMed web page
Wikipedia has a page on publication bias (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to sources of information on schizophrenia and on psychotic disorders (in English and Spanish)
Patient experiences of psychosis, including the effects of medication, are provided by the charity HealthtalkOnline
doi:10.1371/journal.pmed.1001189
PMCID: PMC3308934  PMID: 22448149
22.  Differential use of extended and immediate release quetiapine: a retrospective registry study of Finnish inpatients with schizophrenia spectrum and bipolar disorders 
BMJ Open  2012;2(4):e000915.
Objective
Extended release (XR) and immediate release (IR) quetiapine have differing dosing, titration and plasma concentration profiles. The authors assessed whether the use of quetiapine XR and IR in schizophrenia spectrum disorders (SCZ) and bipolar disorder (BD) differ.
Design
Retrospective non-interventional registry study.
Setting
Secondary healthcare.
Participants
All SCZ and BD (ICD-10 codes F20–F29, F30–F31) patients discharged between June 2008 and June 2010 from a Finnish psychiatric hospital with any use of quetiapine during their inpatient stay.
Primary and secondary outcome measures
Differences in patient characteristics between quetiapine XR and IR users were tested. To assess the profile of XR versus IR patients, logistic regressions were performed.
Results
43 patients used quetiapine XR, 58 used quetiapine IR and 55 used both formulations (n=156). 102 patients were diagnosed with SCZ and 54 with BD, with no significant differences between the quetiapine formulations. The mean daily dose of quetiapine XR was significantly higher than that of quetiapine IR (542 mg vs 328 mg; p<0.001). This was also true for the SCZ subgroup (XR: 593 mg vs IR: 338 mg; p<0.001) and the BD subgroup (XR: 466 mg vs IR: 308 mg; p=0.009). 48% of all quetiapine IR patients used a mean dose of ≤200 mg compared with 2% of XR patients. Injectable antipsychotics were combined with quetiapine IR but not with quetiapine XR (12% vs 0%; p=0.019). At discharge, quetiapine XR was used as monotherapy to a greater extent than IR (79% vs 44%; p=0.003). The odds for quetiapine XR use in hospital were lower with advancing age, substance abuse diagnosis and prior IR use.
Conclusions
Among SCZ and BD inpatients, quetiapine XR was more often used as monotherapy and in significantly higher doses than quetiapine IR. Differential use of the quetiapine formulations appears to depend, at least in part, on patient characteristics.
Article summary
Article focus
Quetiapine exists in an extended (XR) and an immediate release (IR) formulation with different dosing, titration and plasma concentration profiles.
This study assesses whether these differences lead to differential use of the two quetiapine formulations when treating schizophrenia spectrum disorders and bipolar disorder in a routine inpatient care setting.
Key messages
Use of quetiapine XR and IR differs in a routine inpatient care setting: quetiapine XR was used in higher doses and more often as monotherapy when compared with quetiapine IR.
Certain patient characteristics differ between quetiapine XR and IR users: the odds for being treated with quetiapine XR in hospital were lower for older patients, patients with a substance abuse diagnosis, and prior IR use.
Strengths and limitations of this study
The study depicts real-life use patterns of quetiapine XR and IR in an unrestricted patient population: all patients with schizophrenia spectrum disorder or bipolar disorder and any use of quetiapine during their inpatient stay were included.
The results may not be generalisable to other settings as the use of quetiapine may differ in other countries and in the outpatient clinical setting in Finland.
doi:10.1136/bmjopen-2012-000915
PMCID: PMC3391370  PMID: 22761282
23.  Bipolar disorder 
Clinical Evidence  2007;2007:1014.
Introduction
Bipolar disorder, with mood swings between depression and mania, may affect up to 1.5% of adults, and increases the risk of suicide and disability. Most people improve over time, but two thirds may have residual dysfunction, and at least 40% may have recurrent episodes.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with mania associated with bipolar disorder? What are the effects of treatments in bipolar depression? What are the effects of interventions to prevent relapse of mania or bipolar depression? We searched: Medline, Embase, The Cochrane Library and other important databases up to July 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 60 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antidepressants, carbamazepine, chlorpromazine, clonazepam, cognitive therapy, education, family-focused psychoeducation, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, psychological treatments, quetiapine, risperidone, topiramate, valproate, and ziprasidone.
Key Points
Bipolar disorder, with mood swings between depression and mania, may affect up to 1.5% of adults, and increases the risk of suicide and disability. Most people improve over time, but two thirds may have residual dysfunction, and at least 40% may have recurrent episodes.
Lithium reduces symptoms of mania compared with placebo, and seems as effective as haloperidol, carbamazepine, and clonazepam, but can cause adverse effects including hypothyroidism.
Older antipsychotic drugs such as chlorpromazine and haloperidol are widely used to treat mania, but few studies have been done to confirm their efficacy. Olanzapine, valproate, carbamazepine, and risperidone increase the likelihood of response in people with mania compared with placebo, and seem to have similar efficacy as each other, with different adverse-effect profiles. Ziprasidone, quetiapine, and clonazepam may also be beneficial, but few studies have been done to assess the effects of lamotrigine or gabapentin in mania. Topiramate is unlikely to be beneficial in mania. Antidepressants increase treatment response compared with placebo in people with bipolar depression. It is possible that selective serotonin reuptake inhibitors are more effective, and less likely to induce mania, compared with tricyclic antidepressants. Lamotrigine may increase response rates in people with depression compared with placebo, but can cause headache. Quetiapine may also improve depression compared with placebo.We don't know whether lithium, carbamazepine, valproate, or topiramate improve depression in people with bipolar disorder.We don't know whether psychological treatments are effective for people with bipolar depression, as we found no studies.
Lithium reduces relapse in bipolar disorder compared with placebo. Valproate, carbamazepine, and lamotrigine seem as effective as lithium in reducing relapse. Cognitive therapy and patient or family education may reduce the risk of relapse, but studies have given conflicting results.We don't know whether antidepressants can prevent relapse, and they may induce mood instability or manic episodes. Olanzapine may reduce relapse, but long-term use may be associated with weight gain.
PMCID: PMC2943789  PMID: 19454110
24.  Efficacy of Antimanic Treatments: Meta-analysis of Randomized, Controlled Trials 
Neuropsychopharmacology  2010;36(2):375-389.
We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III–IV) bipolar I disorder in 56 drug–placebo comparisons of 17 agents from 38 studies involving 10 800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges' g in 48 trials) was 0.42 (confidence interval (CI): 0.36–0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42–1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p<0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges' g=0.26–0.46); limited data indicated large effect sizes (Hedges' g=0.51–2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy.
doi:10.1038/npp.2010.192
PMCID: PMC3055677  PMID: 20980991
antimanic; antipsychotic; mania; mood stabilizer; placebo; mood; anxiety; stress disorders; clinical pharmacology; clinical trials; psychopharmacology; drug discovery; development; mania; antimanic; mood stabilizer; antipsychotic; placebo
25.  Cardiovascular Side Effects of New Antidepressants and Antipsychotics: New Drugs, old Concerns? 
Current pharmaceutical design  2004;10(20):2463-2475.
The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na+, Ca2+ and K+ channels often leading to life-threatening arrhythmia.
To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors.
Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na+, Ca2+ and K+ channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders.
The primary goal of this review is to shed light on the recently observed clinically important cardiovascular effects of new antidepressants and antipsychotics and discuss the mechanism beyond this phenomenon.
PMCID: PMC2493295  PMID: 15320756
antidepressants; neuroleptics; antipsychotics; QT prolongation; arrhythmia; cardiac ion channels; repolarization

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